A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. Recently, a number of HIV protease inhibitor compounds have been disclosed as being useful in the treatment of infection by HIV and in the treatment of AIDS. These HIV protease inhibitor compounds and their utility in treating HIV and AIDS are described in PCT International Application Publication No. WO 95/16688, published Jun. 22, 1995. More particularly, the compound N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(2-b enzo[b]furanylmethyl)-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneami de, disclosed in Example 3 of WO 95/16688, and referred to herein as "Compound A," is a potent inhibitor of HIV protease and is useful in the treatment of infection by HIV and in the treatment of AIDS or ARC (AIDS related complex), without significant side effects or toxicity. ##STR2## Compound A is prepared according to the procedure of Example 3 in WO 95/16688 or according to the processes disclosed in detail herein. The identification of Compound A as an HIV protease inhibitor useful for treating AIDS was established according to the assays described in WO 95/16688.
Preparation of an acceptable salt of Compound A suitable for pharmaceutical development proved problematic. Numerous attempts to isolate a crystalline salt form of Compound A failed. Eventually, the problem of a pharmaceutically acceptable salt for the HIV protease inhibitor, Compound A, was solved by the synthesis of the HCl (dihydrate) salt. However, the HCl (dihydrate) salt had low solubility in dilute HCl (gastric acid) which resulted in poor oral absorption in animal models. Additionally, the HCl (dihydrate) had an extremely hydrophobic nature, requiring addition of wetting agents during formulation to achieve acceptable dispersion which increases the size of the solid dosage form or the number of pills required to achieve the desired dose, as well as the complexity and cost of the formulation, all of which are undesirable. These problems were solved by identification of the pharmaceutically superior sulfate salt of Compound A of the present invention. More specifically, the sulfate salt of the present invention has substantially improved solubility in dilute HCl (gastric acid) solution which results in much greater oral absorption and bioavailability in animal models. Additionally, the sulfate salt of Compound A is easy to formulate due to its hydrophilic nature, as compared to the HCl salt.